Cariprazine Augmentation in Treatment-Resistant Bipolar Depression: Data from a Retrospective Observational Study

Background Treatment-resistant bipolar depression is one of the leading problems in psychiatry with serious consequences on patients functioning, quality of life and resource utilization. Despite this, there is a lack of consensus on diagnostic criteria and treatment algorithms. Objective The objective of the present study is to assess the acute effectiveness and tolerability of cariprazine in the management of treatment resistant bipolar depression. Methods This is a four weeks retrospective multicentric observational study on patients with treatment resistant bipolar depression receiving cariprazine in augmentation to the current treatment. Cariprazine dosage changed during the follow-up period according to clinical judgment. Since data followed a non-normal distribution, non-parametric tests were used to pursue the analysis. The effectiveness of cariprazine was assessed through the mean change in Hamilton Depression rating scale (HAM-D) scores from baselin Results Fifty-one patients were enrolled. Four patients (7.8%) discontinued cariprazine mainly due to adverse events. Mean cariprazine dose was 1.7 mg/day. The mean HAM-D score decreased significantly from baseline (T0) to week 4 (T4) at each evaluation point. Fourty-five one percent of the patients benefited of cariprazine add-on strategy: 23.5% achieved a clinical response and 21.6% were remitters. Among the completers, 70.6% experienced at least one adverse event. All side effects were mild to moderate. Conclusion Cariprazine seems to be an effective and well tolerated option in the management of patients with treatment resistant bipolar depression.


INTRODUCTION
Depressive episodes represent a major issue in the management and treatment of bipolar disorder (BD).They account for most of the time spent in illness [1][2][3][4] and contribute to the high burden of disability and reduced quality of life, as well as the increased risk of suicide that characterize the disorder [5][6][7].Despite the high prevalence and burden of morbidity, there are limited licensed medications for bipolar depression [8,9], and only a minority of patients achieve remission after adequate treatment.Non-response occurred in 40% of patients after eight weeks of quetiapine [10], and the rate is even higher with other first-line medications such as lithium, lamotrigine or fluoxetine-olanzapine combination [10][11][12][13].
Non-pharmacological approaches, such as transcranial direct current stimulation (tDCS) or repetitive transcranial magnetic stimulation (rTMS), have also been proposed for the treatment of bipolar depression [14,15], with considerable heterogeneity in response rate.
Moreover, the definition of treatment-resistant bipolar depression (TRBD) remains a subject of ongoing debate and lacks a shared operative definition [16].Among the proposed models, Hidalgo-Mazzei and colleagues [9] defined TRBD as "patient failed to reach sustained symptomatic remission at least for 8 consecutive weeks or did not tolerate two different trials at adequate therapeutic doses during 8 weeks either with at least two treatments in monotherapy or at least one treatment monotherapy and one treatment in combination".However, these criteria were difficult to be applied worldwide because many of the drugs listed are not licensed in every country for the treatment of bipolar depression (e.g., lurasidone).Conversely, some licensed drugs are missing.
Cariprazine is an atypical antipsychotic, approved in Europe for the treatment of schizophrenia, that acts as a partial agonist at dopamine D2/D3 (with a higher affinity for D3) and serotonin 5HT1A receptors and as a weak antagonist of 5HT2A receptors [17].Affinity at both D2 and D3 receptors is believed to be involved in strong antipsychotics efficacy as well as treatment advantages such as antidepressant, antianhedonic and pro-cognitive effects; moreover, Partial antagonism at the 5-HT1A receptors may contribute to its antidepressant effects [18,19].Initially licensed by the FDA for the treatment of schizophrenia (1,5-6 mg/day) and acute manic/mixed episodes (3-6 mg/day), cariprazine was subsequently approved for the treatment of bipolar depression (1,5-3 mg/day) and as an adjunctive treatment for unipolar major depressive episodes (1,5-3 mg/day), mainly due to its aforementioned pharmacodynamics properties.
Despite the evidence of efficacy and safety in the treatment of bipolar depression [20], to the best of our knowledge, there is a lack of data on the efficacy of cariprazine in TRBD.Therefore, the aim of this retrospective observational study was to assess the effectiveness and safety of cariprazine in real-world patients with treatment-resistant bipolar depression.

Study Design and Patients
Data was derived from an independent retrospective multicentric observational study aimed at analyzing the acute effectiveness and tolerability of cariprazine in the management of treatment-resistant bipolar depression.
Clinical records of inpatients and outpatients with a diagnosis of bipolar disorder (DSM-5) consecutively admitted or referred to the Psychiatric Unit of San Luigi Gonzaga University Hospital in Orbassano (University of Turin, Italy), the Mental Health Department of Alba and Bra (Cuneo, Italy), the Department of Mental Health of "G.Mazzini" Hospital (Teramo, Italy), the Department of Mental Health of Borgomanero (Novara, Italy) and the Department of Mental Health of Napoli 1 (Napoli, Italy) from June 2022 to February 2023, were analyzed.
The inclusion criteria were the following: a) Age of majority; b) Principal diagnosis of bipolar disorder according to DSM-5 criteria; c) Current major depressive episodes; d) Being treatment resistant according to the operational definition proposed by Murphy and colleagues [21] and already used for studies on TRBD [22] "Tried and failed at least two adequate trials (in dosage achieved and duration) from two classes of antidepressants and two classes of mood stabilizers (including atypical antipsychotic agents)"; e) Being currently treated with at least one mood stabilizers (lithium or valproate) in therapeutic range; f) Receiving cariprazine in augmentation to the current treatment.
All subjects referred to our services did sign a written informed consent to have their clinical data potentially used for teaching or research purposes anonymously treated.A specific request was made to the local Ethical Committee in order to have access to the clinical records of all BD patients who agreed and signed the abovementioned written informed consent.
Cariprazine starting dose and dosage changes were established according to clinical judgment.

Assessment
Socio-demographic, clinical and safety information were collected for each subject from medical reports.Patients underwent control visits according to clinical practice.Clinical symptoms were assessed by means of the Hamilton Depression rating scale (HAM-D), Hamilton Anxiety rating scale (HAM-A), Young Mania Rating Scale (YMRS) and Bipolar depression rating scale (BDRS).For the purpose of this study, medical records were analyzed at the start of treatment with cariprazine and then weekly for four weeks.
All psychiatric diagnoses and clinical assessments were made by a psychiatrist with several years of experience.
The effectiveness of cariprazine was assessed, evaluating the mean change of HAM-D scores from baseline to endpoint.Moreover, qualitative analysis was performed, calculating rates of responders (HAM-D scores mean reduction of at least 50%) and remitters (HAM-D scores < 7).

Statistical Analysis
Sociodemographic and clinical data were presented as mean ± standard deviation for quantitative variables and in percentage (%) for categorical variables.Given a significance level of 0.05, the post hoc power analysis on the sample size of 51 patients showed a statistical power > 95% related to HAM-D mean scores.
Since data followed a non-normal distribution at baseline (Kolmogorov-Smirnov test: 0.139; p: 0.023), non-parametric tests were used.The Wilcoxon test was used to assess the changes in the clinical scales during the observational period.For missing values, a "Last Observation Carried Forward" (LOCF) approach was applied.In addition, patients were categorized into responders/non-responders groups according to the reduction in HAM-D scores and were compared with Kruskal-Wallis non-parametric test for continuous variables and with chi-square (χ 2 ) for categorical variables.Significance was set at p < 0.05.All analyses were performed using IBM SPSS 28.0 software (Armonk, NY, USA).

RESULTS
Fifty-one patients fulfilled the inclusion criteria and were enrolled.Among these, 30 patients (58.8%) were female.The mean age of the sample was 44.08 ± 12.64 years.Thirtyfour patients (66.7%) suffered from bipolar disorder type II, while 17 (33.3%)were from BD type I; the mean age at onset was 25.45 ± 6.98 years.Two-thirds of patients (66.7%) had other comorbid psychiatric disorders.All patients were on mood stabilizers (76.5% were treated with lithium and the remaining 23.5% with valproate), and they were treated with at least one antidepressant of different classes.The mean HAM-D score at baseline was 24.86 ± 4.9.All sociodemographic and clinical characteristics at baseline are shown in Table 1.The mean cariprazine dosage prescribed during the follow-up period was 1.7 mg/day.Forty-seven patients (92.2%) completed the observation period, and four patients (7.8%) dropped out.At week one, two subjects dropped out due to adverse events (AES: agitation and akathisia, respectively), while at week two, one subject discontinued cariprazine due to severe agitation and one subject was lost at follow-up.All dropouts occurred within week two.Among the completers, 36 patients (70.6%) experienced at least one AEs (Fig. 1).

DISCUSSION
To our knowledge, this is the first study focusing on the effectiveness and tolerability of cariprazine in TRBD realworld patients as an add-on strategy.
Treatment-resistant depression is one of the leading problems in psychiatry with serious consequences in terms of patient's functioning and quality of life as well as resource utilization in both Major Depressive Disorder and BD [16,[23][24][25].Despite this, there is a lack of consensus on diagnostic criteria and treatment algorithms for both disorders [23,26,27], thus also preventing the estimation of the true prevalence of the condition.

(A higher resolution/colour version of this figure is available in the electronic copy of the article).
Although not licensed in all countries, cariprazine is one of the so-called third-generation antipsychotics that has shown evidence of efficacy and safety in the treatment of bipolar depression [4], to be included as first-line treatments in guidelines [28].Nevertheless, in Europe, cariprazine can only be used off-label for bipolar depression in clinical practice.
The mean cariprazine dosage (1.7 mg/day) used in our sample was in line with doses used in non-treatment-resistant bipolar depression [20], highlighting how higher dosages are not usually prescribed in bipolar depression, both treatment and non-treatment-resistant.
Our results show that cariprazine can reduce depressive and anxious symptoms in real-world TRBD patients in the short term period.Indeed, at the end of a 4-week observation period, 23.5% of patients met the criteria for a clinical response, and another 21.6% achieved clinical remission.As a result, an average of 45% of patients derived benefits from the cariprazine add-on strategy.A post-hoc analysis of three randomized placebo-controlled studies on the efficacy of cariprazine in (non-resistant) bipolar depression has shown only slightly higher remission rates, 30% and 22.4% for the 1.5 mg/day and 3 mg/day, respectively [4].This difference, although small, can be explained by the fact that real-world patients are more complex than those enrolled in RCTs [29].On the other hand, it could be argued that cariprazine might be effective both in TRBD patients and non-TRDB patients, with efficacy results depending more on other characteristics of the patients, such as symptom dimensions.Indeed, its re- ceptor profile and initial clinical findings provide the basis for believing that cariprazine plays a role in the regulation of motivation and reward-related behavior and may be able to offer improvement in dimensions such as anhedonia and cognition [18,[30][31][32][33].In our sample, the type of bipolar disorder and the patient's psychopharmacological treatments at baseline did not seem to influence the response to therapy.
Concerning tolerability, we found a high rate of AEs (70.6%), especially restlessness/tension, sleepiness, akathisia and tremors, consistent with those most frequently reported in clinical trials with capiprazine in treating bipolar depression [34].Although the side effects were mild to moderate, three out of four patients discontinued the study because of the occurrence of AEs (restlessness and akathisia).In a pooled post-hoc analysis on the safety of cariprazine in bipolar depression, the percentage of patients experiencing any AE was lower (59.5%)[35].However, the higher prevalence of AEs emerged in our real-world sample could be mainly explained by the fact that the strict inclusion and exclusion criteria used in RCTs may exclude most patients encountered in clinical practice [29].
The aforementioned results should be interpreted in light of several limitations of the study, including the retrospective observational design of the study and its very short duration (four weeks).Furthermore, the study lacks a control group of healthy subjects or an active comparator.We acknowledge that the sample size is small, which prevented us from conducting sub-analyses on specific patient characteristics.Furthermore, patients with a high rate of psychiatric comorbidities were included, which may have compromised the study results, such as affecting treatment adherence.However, the comorbidity rate is high in patients with BD, making the study sample representative of real-world TRBD patients.In addition, any dose adjustments required by the concomitant administration of drugs that alter the enzymatic metabolism of cariprazine have not been evaluated.Lastly, tolerability was assessed by reviewing the medical records without reconstructing more specific scales for assessing side effects.

CONCLUSION
Despite all the limitations, this is the first study evaluating the effectiveness and safety of cariprazine in the treatment of patients with treatment-resistance bipolar depression.Given the high prevalence of these conditions and their impact on quality of life and functioning, studies focusing on the pharmacological management of these specific groups of patients in the real world are sorely needed.

ETHICS APPROVAL AND CONSENT TO PARTICI-PATE
The study was approved by local Ethics Committee of San Luigi University Hospital, China.

HUMAN AND ANIMAL RIGHTS
The study was conducted in accordance with the guidelines of Declaration of Helsinki in its most recent version (64 th WMA General Assembly, Fortaleza, Brazil, October 2013).

CONSENT FOR PUBLICATION
All subjects referred to our services did sign a written informed consent to have their clinical data potentially used for teaching or research purposes, anonymously treated.

STANDARDS OF REPORTING
STROBE guidelines and methodology were followed.

Fig. ( 1
Fig. (1).Most common adverse events in completers (N: 47).Adverse events <5%: insomnia, constipation, headache, rigidity, weight gain.(A higher resolution/colour version of this figure is available in the electronic copy of the article).

Fig. ( 2 ).
Fig. (2).Mean reduction of Hamilton Depression rating scales (HAM-D) scores during follow-up.*p < 0.05.(A higher resolution/colour version of this figure is available in the electronic copy of the article).